Successful Asfotase Alfa Treatment in an Adult Dialysis Patient With Childhood-Onset Hypophosphatasia

Hypophosphatasia is an inherited disease characterized by reduced alkaline phosphatase activity, extracellular accumulation of inorganic pyrophosphate, and impaired bone mineralization. Asfotase alfa (AA) is a recombinant human alkaline phosphatase therapy approved for treatment of pediatric-onset hypophosphatasia. Studies show promising outcome in AA-treated children with hypophosphatasia; however, data on adults with pediatric-onset hypophosphatasia are scarce. We report on a 59-year-old woman with childhood- onset hypophosphatasia and a history of multiple fractures and orthopedic procedures. Owing to renal failure (histological diagnosis: focal segmental glomerulosclerosis), hemodialysis was started in 2013. By the end of 2015, the patient was unable to walk, could only stand for 30 seconds, and was completely dependent on help for activities of daily living. After 13 months of AA therapy, the patient showed a dramatic increase in quality of life (increased mobility), reduction in pain medication, and a significant improvement in bone mineralization throughout the skeleton, including consolidation of existing fractures and no occurrence of new fractures. This case report demonstrates a relevant therapeutic success of AA treatment in an adult hemodialysis patient with childhood onset of hypophosphatasia

Improving metaheuristic performance by evolving a variable fitness function.

In this paper we study a complex real world workforce scheduling problem. We apply constructive search and variable neighbourhood search (VNS) metaheuristics and enhance these methods by using a variable fitness function. The variable fitness function (VFF) uses an evolutionary approach to evolve weights for each of the (multiple) objectives. The variable fitness function can potentially enhance any search based optimisation heuristic where multiple objectives can be defined through evolutionary changes in the search direction. We show that the VFF significantly improves performance of constructive and VNS approaches on training problems, and ¿learn¿ problem features which enhance the performance on unseen test problem instances

Dynamic optimisation of preventative and corrective maintenance schedules for a large scale urban drainage system

Gully pots or storm drains are located at the side of roads to provide drainage for surface water. We consider gully pot maintenance as a risk-driven maintenance problem. We explore policies for preventative and corrective maintenance actions, and build optimised routes for maintenance vehicles. Our solutions take the risk impact of gully pot failure and its failure behaviour into account, in the presence of factors such as location, season and current status. The aim is to determine a maintenance policy that can automatically adjust its scheduling strategy in line with changes in the local environment, to minimise the surface flooding risk due to clogged gully pots. We introduce a rolling planning strategy, solved by a hyper-heuristic method. Results show the behaviour and strength of the automated adjustment in a range of real-world scenarios

Metastatic Pheochromocytoma and Paraganglioma: Somatostatin Receptor 2 Expression, Genetics, and Therapeutic Responses

CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) with pathogenic mutations in the succinate dehydrogenase subunit B (SDHB) are associated with a high metastatic risk. Somatostatin receptor 2 (SSTR2)-dependent imaging is the most sensitive imaging modality for SDHB-related PPGLs, suggesting that SSTR2 expression is a significant cell surface therapeutic biomarker of such tumors. OBJECTIVE: Exploration of the relationship between SSTR2 immunoreactivity and SDHB immunoreactivity, mutational status, and clinical behavior of PPGLs. Evaluation of SSTR-based therapies in metastatic PPGLs. METHODS: Retrospective analysis of a multicenter cohort of PPGLs at 6 specialized Endocrine Tumor Centers in Germany, The Netherlands, and Switzerland. Patients with PPGLs participating in the ENSAT registry were included. Clinical data were extracted from medical records, and immunohistochemistry (IHC) for SDHB and SSTR2 was performed in patients with available tumor tissue. Immunoreactivity of SSTR2 was investigated using Volante scores. The main outcome measure was the association of SSTR2 IHC positivity with genetic and clinical-pathological features of PPGLs. RESULTS: Of 202 patients with PPGLs, 50% were SSTR2 positive. SSTR2 positivity was significantly associated with SDHB- and SDHx-related PPGLs, with the strongest SSTR2 staining intensity in SDHB-related PPGLs (P = .01). Moreover, SSTR2 expression was significantly associated with metastatic disease independent of SDHB/SDHx mutation status (P < .001). In metastatic PPGLs, the disease control rate with first-line SSTR-based radionuclide therapy was 67% (n = 22, n = 11 SDHx), and with first-line "cold" somatostatin analogs 100% (n = 6, n = 3 SDHx). CONCLUSION: SSTR2 expression was independently associated with SDHB/SDHx mutations and metastatic disease. We confirm a high disease control rate of somatostatin receptor-based therapies in metastatic PPGLs

An empirical study of hyperheuristics for managing very large sets of low level heuristics

Hyperheuristics give us the appealing possibility of abstracting the solution method from the problem, since our hyperheuristic, at each decision point, chooses between different low level heuristics rather than different solutions as is usually the case for metaheuristics. By assembling low level heuristics from parameterised components we may create hundreds or thousands of low level heuristics, and there is increasing evidence that this is effective in dealing with every eventuality that may arise when solving different combinatorial optimisation problem instances since at each iteration the solution landscape is amenable to at least one of the low level heuristics. However, the large number of low level heuristics means that the hyperheuristic has to intelligently select the correct low level heuristic to use, to make best use of available CPU time. This paper empirically investigates several hyperheuristics designed for large collections of low level heuristics and adapts other hyperheuristics from the literature to cope with these large sets of low level heuristics on a difficult real- world workforce scheduling problem. In the process we empirically investigate a wide range of approaches for setting tabu tenure in hyperheuristic methods, for a complex real-world problem. The results show that the hyperheuristic methods described provide a good way to trade off CPU time and solution quality

The Saline Infusion Test for Primary Aldosteronism: Implications of Immunoassay Inaccuracy

CONTEXT: Diagnosis of primary aldosteronism (PA) for many patients depends on positive results for the saline infusion test (SIT). Plasma aldosterone is often measured by immunoassays, which can return inaccurate results. OBJECTIVE: This study aimed to establish whether differences in aldosterone measurements by immunoassay versus mass spectrometry (MS) might impact confirmatory testing for PA. METHODS: This study, involving 240 patients tested using the SIT at 5 tertiary care centers, assessed discordance between immunoassay and MS-based measurements of plasma aldosterone. RESULTS: Plasma aldosterone measured by Liaison and iSYS immunoassays were respectively 86% and 58% higher than determined by MS. With an immunoassay-based SIT cutoff for aldosterone of 170 pmol/L, 78 and 162 patients had, respectivel, negative and positive results. All former patients had MS-based measurements of aldosterone < 117 pmol/L, below MS-based cutoffs of 162 pmol/L. Among the 162 patients with pathogenic SIT results, MS returned nonpathologic results in 62, including 32 under 117 pmol/L. Repeat measurements by an independent MS method confirmed nonpathogenic results in 53 patients with discordant results. Patients with discordant results showed a higher (P < 0.0001) prevalence of nonlateralized than lateralized adrenal aldosterone production than patients with concordant results (83% vs 28%). Among patients with nonlateralized aldosterone production, 66% had discordant results. Discordance was more prevalent for the Liaison than iSYS immunoassay (32% vs 16%; P = 0.0065) and was eliminated by plasma purification to remove interferents. CONCLUSION: These findings raise concerns about the validity of immunoassay-based diagnosis of PA in over 60% of patients with presumed bilateral disease. We provide a simple solution to minimize immunoassay inaccuracy-associated misdiagnosis of PA